Field of the Invention
Embodiments of the invention generally relate to compounds that are useful for the treatment and/or prevention of neurodegenerative disorders such as Alzheimer's disease. In particular, the invention provides novel hybrid compounds of curcumin and melatonin, and uses thereof.
Background of the Invention
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. It is estimated that 5.2 million Americans of all ages and up to 30 million individuals worldwide are affected by AD1. In addition to the human cost, more than $200 billion is spent annually on AD treatment, significantly exacerbating problems with the overextended U.S. health care economy. Current AD treatments provide mainly symptomatic relief and there are no agents available to delay or cure this disease. The etiology of AD still remains elusive and multiple factors including beta-amyloid (Aβ) aggregates2, soluble Aβ oligomers (AβOs)3-5, dyshomeostasis of biometals, oxidative stress, and neuroinflammation6,7, have been implicated in the development of AD. Recently, the multifunctional strategy of small molecule design has attracted extensive attention in overcoming the limitations of the traditional “one molecule, one target” approach in the development of effective AD treatments, given its multifactorial nature8,9. However, rational design of small molecules with therapeutic polypharmacology has always been a challenging task. Therefore, an efficient strategy that helps to identify novel chemical templates would be of great value in surmounting the paucity of effective disease-modifying agents in the pipeline of AD therapeutics.
Natural products have proven to be reliable resources in providing effective therapeutics for a variety of diseases. Curcumin and melatonin have been implicated as potential AD treatment agents by extensive studies10-13. Curcumin (1, FIG. 1), a yellow spice and pigment isolated from the rhizome of Curcuma longa, has been traditionally and widely used as a food coloring additive. Recently, curcumin has attracted extensive attention in biomedical research as multiple biological activities of curcumin have been revealed including antioxidant, anti-inflammatory, biometal chelating, anti-proliferative, and anti-Aβ activities, among others. As oxidative stress, neuroinflammation, dyshomeostasis of metals, and Aβ have been implicated in the pathology of AD, 1 has been tested in various AD models. Both in vitro and in vivo studies have shown that 1 prevented Aβ-induced toxicity, lowered the level of Aβ in the brain as well as the level of inflammatory cytokines and oxidative stress, thus demonstrating the potential of 1 as a promising candidate for treating human AD14. However, due to its poor solubility, bioavailability, and gastrointestinal side effects, further development of 1 as an effective agent for AD is limited. Therefore new analogs of 1 with improved efficacy and pharmacokinetic properties would be of great value for AD patients.
Melatonin (2, FIG. 1), the major secretory product of the pineal gland, plays an essential role in the regulation of circadian rhythms15. In addition, 2 can be produced in various tissues and organs, and participates in diverse functions through both receptor-dependent and independent ways, including free radical scavenging, immune response, and mood monitoring, among others13, 16. Notably, circadian dysfunction and the reduction of 2 have been observed in AD, thus suggesting the potential of 2 in AD treatment17,18. Indeed, 2 has been tested as a potential treatment for AD19. In transgenic AD mouse models, 2 has also been shown to improve cognition and reduce Aβ deposition and neuroinflammation19,20. Clinical studies of 2 in AD patients also suggested beneficial effects, especially in sleep quality, reduced sundowning, etc.21 However, more studies are needed to explore and investigate the usefulness of 2 as a treatment for AD. Furthermore, 2 has a relatively short half-life (<30 min), thus novel analogs that retain the multifunctional properties of 2, with improved pharmacokinetic properties, are needed for further investigation and development.